HCV infects 170 million persons worldwide and causes significant morbidity in developed and developing countries. Therapies for HCV infection have improved recently, but still fail in many persons and are unavailable for most infected individuals worldwide. Therefore understanding natural immunity to this infection and the development of prophylactic vaccines remain urgent goals. To this end, it will be essential to better understand the early events during acute HCV infection, as this is the exclusive time at which spontaneous clearance of viremia has been observed to occur. Our understanding of the early events during acute human HCV infection is limited because of the difficulties in identifying persons with acute infection for study, and because of previous limitations in the methodologies used to analyze the immune response and viral evolution. Together with the National Reference Center for Viral Hepatitis at the Oswaldo Cruz Institute in Rio de Janeiro/Brazil we have already identified more than 30 cases of acute symptomatic HCV. Furthermore, persons with non-symptomatic disease will also be recruited. In addition to these subjects who were all infected through mechanisms other than iv drug use, we also are studying the problem of acute HCV infection in incarcerated intravenous drug users, an important underserved population with a high risk of HCV exposure. To study the mechanisms leading to viral eradication or persistence we have developed highly sensitive and specific immunologic assays that allow for the longitudinal qualitative and quantitative assessment of HCV-specific T-cell immune responses. We will complement these studies by full-length sequencing of autologous virus to determine the impact of the immune response on viral evolution as well as mechanisms of viral escape and adaptation. Potential deficits in the innate immune response against HCV are another focus of this application, and we have already started collaborations beyond this Center to investigate additional mechanisms not covered here, e.g. the role of neutralizing antibodies. In summary, we will collect comprehensive clinical, immunological and virological data from a large group of individuals with acute HCV infection, representing different routes of transmission, different clinical presentations and different outcomes of infection. We are confident that the comprehensive description of the complex interactions between human immune system and the virus will result in a significantly improved understanding of the mechanisms involved in viral control and persistence and will facilitate future preventative and therapeutic interventions against HCV infection.